Suicidal inactivation of human dihydropyrimidine dehydrogenase by (E)-5-(2-bromovinyl)uracil derived from the antiviral, sorivudine.
An enzymatic study was performed to clarify the mechanism of 18 acute deaths in patients who had received the new oral antiviral drug, sorivudine (SRV), during anticancer chemotherapy with 5-fluorouracil (5-FU) prodrugs. Human dihydropyrimidine dehydrogenase (hDPD), playing a key role in the liver as the rate-limiting enzyme in catabolism of 5-FU, was expressed in E. coli, purified and incubated in the presence of NADPH with SRV or (E)-5-(2-bromovinyl)uracil (BVU), a metabolite of SRV produced by human gut flora. hDPD was rapidly and irreversibly inactivated by BVU, but not by SRV. Radioactivity of [14C]BVU was incorporated into hDPD in the presence of NADPH in a manner reciprocal to the enzyme inactivation. In the absence of NADPH, hDPD was not inactivated by BVU, nor radiolabeled with [14C]BVU. Thus, as we demonstrated previously with studies using the rat, the acute deaths were strongly suggested to be attributable to markedly elevated tissue 5-FU levels which were responsible for irreversible inhibition of hDPD by covalent binding of a reduced form of BVU as a suicide inactivator.
Ogura
K
K
Department of Drug Metabolism and Molecular Toxicology, School of Pharmacy, Tokyo University of Pharmacy and Life Science, Japan.
Nishiyama
T
T
Takubo
H
H
Kato
A
A
Okuda
H
H
Arakawa
K
K
Fukushima
M
M
Nagayama
S
S
Kawaguchi
Y
Y
Watabe
T
T
D000998:Antiviral Agents / Q000378:metabolism / Q000633:toxicity*; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives* / Q000378:metabolism; D001976:Bromouracil / Q000031:analogs & derivatives* / Q000633:toxicity; D042943:Dihydrouracil Dehydrogenase (NADP); D004305:Dose-Response Relationship, Drug; D006801:Humans; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors
D000998:Antiviral Agents; D011994:Recombinant Proteins; D001086:Arabinofuranosyluracil; D001976:Bromouracil; C046140:5-(2-bromovinyl)uracil; C031368:sorivudine; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP)